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United States Patent 3-AN]LINO-2H,1,4-BENZOTHIAZINES Markus Zimmermann,Riehen, Switzerland, assignor to G. D. Searle & Co., Chicago, 11]., acorporation of Delaware No Drawing. Application September 13, 1956Serial No. 609,541

6 Claims. (Cl. 260-443) This invention relates to anilino derivatives of2H,1,4- benzothiazin-3(4H)-one of the formula QIZL Q" and acid additionsalts thereof wherein X is hydrogen, halogen, hydroxy or lower alkoxy.

The compounds of the invention are prepared by reacting aniline or anappropriate derivative thereof with 3-bromo or3-chloro-2H,1,4-benzothiazin-3(4H)-one. The reaction may be carried outas desired with or without the use of inert diluents such as benzene,toluene, carbon tetrachloride, ethylene dichloride and the like and atroom temperatures but preferably at moderately ele vated temperaturessuch as the reflux temperatures of the inert diluents.

Alternatively, the compounds of the invention are obtained by reactingtogether 2H,l,4-benzothiazin-3 (4H)- one, an agent such as phosphoroustribromide or trichloride and the appropriate aniline with or withoutinert diluent as desired and preferably at moderately elevatedtemperature.

The product of the reaction is isolated as desired either as the freebase or in the form of its acid addition salts.

For isolation as the free base, the reaction mixture is diluted withwater, made alkaline and extracted with a volatile solvent such asether. After drying, the solvent is removed and the residue crystallizedto yield the free base.

Acid addition salts of the free base are prepared by dissolving the basein a solvent such as ethanol, ethyl acetate, isopropanol or mixturesthereof and adding excess isopropanolic solution of the desired acid.Suitable acids are the hydrohalogen acids such as hydrochloric orhydrobromic and acids such as sulfuric, acetic, citric, tartaric and thelike.

In addition to aniline, suitable derivatives thereof may be used and areselected from substituted anilines e. g. the halogenated anilines suchas orthoand para-chloroor bromoanilines, 2,4-dichloroaniline, p-acyloxyesters of aniline-such as p-acetoxyaniline and p-lower alkoxyanilines.

The compounds of the invention are valuable because of their desirablepharmacological activity as spasmolytic agents. In addition,3-anilino-2I-L1,4-benzothiazine promotes the excretion of sodium andthus serves as a sodium diuretic. The compounds are relatively insolublein water but are readily soluble in common solvents such as alcohol,ether, benzyl alcohol and the like. They may be administered orally intablet form or may be given parenterally.

The examples which follow illustrate the invention in 2,824,101 PatentedFeb. 18, 1958 greater detail but it is to be understood that theinvention is not limited thereto. In the examples, parts by weight bearthe same relation to parts by volume as kilograms to liters.Temperatures are expressed in degrees centigrade.

Example 1 3.2 parts by weight of 2H,l,4-benzothiazin-3 (4H)-one, 1.9parts by volume of aniline and 25 parts by volume of phosphoroustrichloride are mixed while cooling with ice. The mixture is then warmedto -80 for about 4 hours. The reaction mixture is poured on ice, madealkaline with saturated sodium carbonate solution, extracted with ether,the ether extract dried with sodium sulfate and the ether evaporatedoff. The residue is recrystallized from aqueous ethanol with the use ofde colorizing carbon to yield 3-anilino-2H,1,4-benzothiazine, M. P.165-168.

By substituting m-chloroaniline for the aniline used above there isobtained 3-(m-chloroanilino)-2I-l,1,4-benzothiazine, M. P. 151-153".

By substituting 3 grams of p-acetoxyaniline for the aniline used abovethere is obtained S-(p-acetoxy-anilin0)-2H,1,4-benzothiazine.3-(p-hydroxyaniline)-2H,1, 4-benzothiazine is obtained by dissolving theacetoxy derivative in alcohol containing a small quantity of sodiumethylate and allowing the mixture to stand for 3 hours at roomtemperature, weakly acidifying with hydrochloric acid, adding ethylacetate, filtering to remove the precipitated sodium chloride andevaporating off the solvent.

ExampleZ 6.5 parts by weight of 2H,l,4-benzothiazin-3 (4H)-one, 5.3parts by volume of o-chloroaniline and 25 parts by volume of phosphoroustrichloride are mixed white cooling and then heated at for three hours.The reaction mixture is quenched in ice, the mixture made alkaline,extracted with ether, the ether extract dried over sodium sulfate andthe ether removed. The residue is dissolved in ethanol-ethyl acetate towhich is added excess isopropanolic hydrogen chloride. After standingovernight, the precipitate is filtered off and recrystallized fromethanol-ethyl acetate to yield 3-(o-chloroanilino)- 2H,l,4-benzothiazinehydrochloride, M. P. 146150.

By substituting p-anisidine for the o-chloroaniline used above, there isobtained 3-(p-methoxyanilino)-2H,1,4- benzothiazine hydrochloride, M. P.208-210 (dec.).

What is claimed is:

1. A compound selected from the group consisting of compounds having theformula and non-toxic acid addition salts thereof wherein X is selectedfrom the group consisting of hydrogen, halogen, hydroxy, (loweralkyl)COO- and lower alkoxy.

2. 3-anilino-2H,1,4-benzothiazine. d3.3-(o-chloroanilino)-2H,1,4-benzothiazine hydrochlon e.

4. 3-(m-chloroanilino)-2H,1,4-benzothiazine.

5. 3-(p-hydroxyanilino)-2H,l,4-benzothiazine.

6. S-(p-methoxyanilino)-2H,1,4-benzothiazine hydrochloride.

References Cited in the file of this patent 18lsieilsteinz -OrganischeChemie," vol. 27 (1937), page

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THEFORMULA